Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1?-bicyclohexyl-2-carboxylate, a muscarinic antagonist

Bugno, Cristina Di; Colombani, Spartaco Mauro; Dapporto, P.; Garzelli, G; Giorgi, Raffaello; Paoli, Paola; Subissi, Alessandro; Turbanti, L

doi:10.1002/(sici)1520-636x(1997)9:8<713::aid-chir1>3.0.co;2-6

Cited by 9 publications

(2 citation statements)

References 22 publications

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“…At 72% conversion the enantiomeric excess of the residual diol was maximised (1 R ,2 S - 143 , 85%ee), whereas at 28% conversion the enantiomeric excess of the monoacetate was maximised ( 144 , 78%ee) [ 155 ] at the expense of poor yields in both cases. Consequently in subsequent work, the rociverine ( 145 ) was resolved by diastereomeric salt formation with tartaric or di- O -benzoyl-tartaric acid [ 156 ].…”

Section: Muscarinic Antagonistsmentioning

confidence: 99%

Muscarinic Receptor Agonists and Antagonists

2001

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A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

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Section: Muscarinic Antagonistsmentioning

confidence: 99%

Muscarinic Receptor Agonists and Antagonists

2001

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“…However, preliminary biological results suggest that ( S )-oxybutynin displays an improved therapeutic profile compared to its racemic counterpart, and it is currently in phase III clinical trials. Like a majority of the muscarinic receptor antagonists, oxybutynin is composed of a tertiary α-hydroxy acid as a key component . Recently, we disclosed an attractive process for the production of enantiopure ( S )-acid 1 utilizing the addition of cyclohexyl Grignard to aminoindanol-derived ketoesters .…”

Section: Introductionmentioning

confidence: 99%

Chiral Mandelic Acid Template Provides a Highly Practical Solution for (S)-Oxybutynin Synthesis

et al. 2000

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Enantioselective Rhodium‐Catalyzed Addition of Arylboronic Acids to α‐Ketoesters

et al. 2008

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The transition-metal-catalyzed asymmetric addition of organometallic reagents to carbonyl compounds to produce enantiomer-enriched secondary or tertiary alcohols is a powerful tool for the construction of carbon-carbon bonds. Many organometallic reagents have been successfully used in this addition reaction.[1] However, a drawback for most organometallic reagents is their sensitivity to moisture and air, both of which impede the practical applications of these asymmetric carbon-carbon bond-forming reactions. As an exception, arylboronic acids are very stable to air and moisture. The catalytic enantioselective addition of arylboronic acids to carbonyl compounds has became a current focus for research, [1d] and a number of efficient chiral catalysts have been developed for the catalytic asymmetric addition of arylboronic acids to aldehydes [2] and aldimines.[3] However, the catalytic asymmetric addition of arylboronic acids to ketones, which are less active relative to aldehydes and aldimines, is more difficult, and only limited progress has been achieved. In 2006, Hayashi et al. reported the asymmetric addition of arylboronic acids to isatins, cyclic aketoamides, catalyzed by a rhodium/MeO-Mop (MeO-Mop = 2-methoxy-2'-diphenylphosphino-1,1'-binaphthyl) complex in high enantioselectivities (72-91 % ee).[4] By using a chiral phosphoramidite ligand derived from H 8 -binol (binol = 2,2'-dihydroxy-1,1'-binaphthyl), de Vries, Minnard, Feringa and et al. obtained 55 % ee in the same reaction.[5] The chiral phosphoramidite ligand was also used in the asymmetric addition of arylboronic acids to trifluoromethyl ketones with good enantioselectivities (50-83 % ee).[6] The intramolecular asymmetric addition of arylboronic acids to ketones catalyzed by a cationic palladium complex of binap (binap = 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl) to give cyclic tertiary alcohols in high enantioselectivities (53-96 % ee) was reported by Lu et al. [7] To the best of our knowledge, the catalytic enantioselective addition of arylboronic acids to aketoesters to provide tertiary a-hydroxyesters has not yet been reported. [8] In the search for highly efficient methods to construct chiral 2-hydroxydiarylacetates, desirable chiral intermediates for the synthesis of antagonists of muscarinic receptors, [9] we became interested in the enantioselective addition of arylboronic acids to the a-aryl-and a-alkenyl-a-ketoesters. The Rh I /ShiP (ShiP = aryl(1,1'-spirobiindane-7,7'-diyl)phosphite) catalysts (1) recently developed by us [2c, 3b] were found to be highly efficient for this addition reaction to provide chiral tertiary a-hydroxyesters [10] in good yields and high enantiomeric excesses (up to 93 % ee).Preliminary experiments were carried out in H 2 O with catalyst generated in situ from 1.5 mol % [{RhCl-(CH 2 CH 2 ) 2 } 2 ][11] and 6 mol % (S)-1 a in the presence of two equivalents of LiF.[12] The addition of phenylboronic acid to ethyl 2-(4-chlorophenyl)-2-oxoacetate (2 a) at room temperature for 48 hours afforded tertiary a-hydroxyeste...

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Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1?-bicyclohexyl-2-carboxylate, a muscarinic antagonist

Cited by 9 publications

References 22 publications

Muscarinic Receptor Agonists and Antagonists

Muscarinic Receptor Agonists and Antagonists

Chiral Mandelic Acid Template Provides a Highly Practical Solution for (S)-Oxybutynin Synthesis

Enantioselective Rhodium‐Catalyzed Addition of Arylboronic Acids to α‐Ketoesters

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